Statins as potential therapeutic agents for handling Nephrogenic Diabetes Insipidus

Abstract of the project and progress report X-linked nephrogenic diabetes insipidus (X-NDI) is a rare disease characterized by resistance of the kidney to the action of the antidiuretic hormone arginine-vasopressin (AVP) and is accompanied by severe polyuria and risk of dehydration. It is caused by inactivating mutations in the AVP type 2 receptor (V2R) gene that prevent the AVP-induced trafficking of the water channel AQP2 to the luminal plasma membrane of the kidney collecting duct (CD), and, consequently, reduces kidney concentration ability. In addition, as AVP also regulates AQP2 gene transcription, AQP2 protein is very low in NDI. This represents one of the principal limitations toward the establishment of an AQP2-targeted therapy that could bypass AVP signaling in NDI patients. Even if expressed at the plasma membrane, the residual amount of AQP2 expressed by an NDI patient might be insufficient to guarantee proper water reabsorption. These considerations prompted us to explore alternative signaling pathways that could restore physiological levels of AQP2 in the CD. One of the best candidates that could fulfill this purpose is the secretin receptor (SCTR), a G-proteins-coupled receptor (GPCR) that, like V2R, elevates intracellular cAMP levels upon binding its ligand secretin (SCT), a hormone physiologically released by the intestinal mucosa. We report here that SCTR is functionally expressed at the basolateral membrane of kidney collecting duct principal cells. To investigate a possible beneficial effect of SCT on NDI phenotype, X-NDI mice, the only viable mouse model of X-linked NDI, were subcutaneously infused with SCT (1nmol/Kg/day, via osmotic minipumps) for 14 days. Urinary parameters were not altered in SCT-infused animals. Interestingly, however, SCT significantly increased AQP2 levels in the CD, although the protein was mostly accumulated in the intracellular storage vesicles and hardly detectable at the plasma membrane. We previously reported that fluvastatin (Flu) treatment, mimicking the action of AVP, transiently increases AQP2 abundance at the luminal membrane of the kidney CD in vivo in wild type mice in the absence of AVP stimulation. SCT-infused X-NDI mice were injected intraperitoneally with Flu (50 mg/Kg). Diuresis and urine osmolality were monitored for 6 hours after Flu injection. Interestingly, Flu was able to potentiate the effect of SCT: cumulative diuresis was reduced by nearly 90% in mice treated with SCT+Flu and, accordingly, urine osmolality almost doubled in the same interval of time. Immunofluorescence confirmed that SCT increased intracellular stores of AQP2 and the addition of Flu promoted AQP2 accumulation at the plasma membrane. Taken together these data strongly indicate that the combination of SCT and Flu might represent a new and effective pharmacological treatment for X-NDI.